Spatiotemporal spread of tick-borne encephalitis in the EU/EEA, 2012 to 2020

Background Tick-borne encephalitis (TBE) is a vaccine-preventable disease involving the central nervous system. TBE became a notifiable disease on the EU/EEA level in 2012. Aim We aimed to provide an updated epidemiological assessment of TBE in the EU/EEA, focusing on spatiotemporal changes. Methods We performed a descriptive analysis of case characteristics, time and location using data of human TBE cases reported by EU/EEA countries to the European Centre for Disease Prevention and Control with disease onset in 2012–2020. We analysed data at EU/EEA, national, and subnational levels and calculated notification rates using Eurostat population data. Regression models were used for temporal analysis. Results From 2012 to 2020, 19 countries reported 29,974 TBE cases, of which 24,629 (98.6%) were autochthonous. Czechia, Germany and Lithuania reported 52.9% of all cases. The highest notification rates were recorded in Lithuania, Latvia, and Estonia (16.2, 9.5 and 7.5 cases/100,000 population, respectively). Fifty regions from 10 countries, had a notification rate ≥ 5/100,000. There was an increasing trend in number of cases during the study period with an estimated 0.053 additional TBE cases every week. In 2020, 11.5% more TBE cases were reported than predicted based on data from 2016 to 2019. A geographical spread of cases was observed, particularly in regions situated north-west of known endemic regions. Conclusion A close monitoring of ongoing changes to the TBE epidemiological situation in Europe can support the timely adaption of vaccination recommendations. Further analyses to identify populations and geographical areas where vaccination programmes can be of benefit are needed.

Supplementary material S1. Study flowchart EU/EEA member states have reported 26,043 TBE cases with onset between 1 January 2012 and 31 December 2020. After data cleaning, 855 cases had an unknown importation status and were excluded. As described in the methods, 318 cases reported by Finland with missing importation status were classified as autochthonous in agreement with the Finnish Institute for Health and Welfare. A total of 214 cases were additionally excluded since they were reported by countries that did not report casebased data every year. These countries are Belgium, Bulgaria, Croatia, Cyprus, Denmark, Italy, Luxembourg, Malta, Portugal, the United Kingdom, Iceland, and Liechtenstein.

Supplementary material S2. Imputation rules spatial analysis
Whenever the place of infection was not available for autochthonous cases, the place of residence and the place of notification were taken as proxies (in respective order, depending on availability). To support this imputation, the different location variables were compared where possible. Comparison between the place of infection and place of residence shows a concordance of 90.21% at NUTS-3 level (n = 16,999) and 94.56% at NUTS-2 level (n = 18,002). Comparison between the place of infection and the place of notification shows a concordance of 90.48% at NUTS-3 level (n = 15,781) and 94.45% at NUTS-2 level (n = 18,004). Table 1 and 2 indicate that the concordance levels are similar in the different countries, except for Latvia. However, it should be noted that very few cases could be tested in this country. The extent to which TBE cases from different countries have been affected by the imputation is presented in Table 3. In addition, the table illustrates the number of cases without geographical information at the NUTS-2 or NUTS-3 level.

Supplementary material S3. Verification of tick-borne encephalitis virus transmission in scientific literature
Place of infection was the primary variable of interest for all cases in spatial analyses. Whenever this variable was not available for autochthonous cases, place of residence and place of notification were taken as proxies (in respective order, depending on availability). To minimize bias, only NUTS regions with verified TBE virus transmission were eligible as a proxy. Even though the following NUTS levels were not originally reported as place of infection in our database (i.e., no documented TBE transmission in the TESSy database), they were accepted as proxies based on the cited scientific evidence indicating TBE virus transmission: -Latvia: Rīga (LV006), Vidzeme (LV008), Zemgale (LV009) [1] -Poland: Nowosądecki (PL218), Bielski (PL225), Gorzowski (PL431), Trójmiejski (PL633) [2,3] -Slovenia: Savinjska (SI034), Zasavska (SI035), Posavska (SI036), Obalno-kraška (SI044) [4].

Supplementary material S4. Regional spatial analysis
We assessed 24,974 TBE cases which were reported by nineteen EU/EEA countries between 2012 and 2020. Out of those, 24,629 were autochthonous cases for which a geographical analysis at regional level was performed. The following countries reported geographical information at NUTS-3 level: Czechia, Germany, Estonia, Greece, Spain, Finland, Hungary, Ireland, Lithuania, Latvia, Poland, Romania, Sweden, Slovenia, and Slovakia. Austria and France reported geographical information at NUTS-2 level. The Netherlands and Norway only reported cases at country level and are therefore not included in the regional analysis. As a result, 786 different NUTS levels were evaluated in the geographical analysis of autochthonous cases.
A total of 53 autochthonous cases did not have information at regional level and are therefore not included in the regional analysis. Table 1 provides an overview of how these cases are distributed across the reporting countries and the study years.
Supplementary Table S4. Number of cases with missing geographical information at regional level

Supplementary material S5. Notification rate per year and region
The